Full Text Journal Articles by
Author Ryan Paxman


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Pharmacologic targeting of plasma cell endoplasmic reticulum proteostasis to reduce amyloidogenic light chain secretion.

Bibiana Rius, Jaleh S Mesgarzadeh, Isabelle C Romine, Ryan J Paxman, Jeffery W Kelly, R Luke Wiseman,

Light chain (LC) amyloidosis (AL) involves the toxic aggregation of amyloidogenic immunoglobulin LCs secreted from a clonal expansion of diseased plasma cells. Current AL treatments use chemotherapeutics to ablate the AL plasma cell population. However, no treatments are available that directly reduce the toxic LC aggregation involved in AL pathogenesis. ... Read more >>

Blood Adv (Blood advances)
[2021, 5(4):1037-1049]

Cited: 1 time

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Blinded potency comparison of transthyretin kinetic stabilisers by subunit exchange in human plasma.

Luke T Nelson, Ryan J Paxman, Jin Xu, Bill Webb, Evan T Powers, Jeffery W Kelly,

Transthyretin (TTR) tetramer dissociation is rate limiting for aggregation and subunit exchange. Slowing of TTR tetramer dissociation <i>via</i> kinetic stabiliser binding slows cardiomyopathy progression. Quadruplicate subunit exchange comparisons of the drug candidate AG10, and the drugs tolcapone, diflunisal, and tafamidis were carried out at 1, 5, 10, 20 and 30 µM ... Read more >>

Amyloid (Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis)
[2021, 28(1):24-29]

Cited: 1 time

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Pharmacologic IRE1/XBP1s activation confers targeted ER proteostasis reprogramming.

Julia M D Grandjean, Aparajita Madhavan, Lauren Cech, Bryan O Seguinot, Ryan J Paxman, Emery Smith, Louis Scampavia, Evan T Powers, Christina B Cooley, Lars Plate, Timothy P Spicer, Jeffery W Kelly, R Luke Wiseman,

Activation of the IRE1/XBP1s signaling arm of the unfolded protein response (UPR) is a promising strategy to correct defects in endoplasmic reticulum (ER) proteostasis implicated in diverse diseases. However, no pharmacologic activators of this pathway identified to date are suitable for ER proteostasis remodeling through selective activation of IRE1/XBP1s signaling. ... Read more >>

Nat Chem Biol (Nature chemical biology)
[2020, 16(10):1052-1061]

Cited: 13 times

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ER Proteostasis Regulators Reduce Amyloidogenic Light Chain Secretion Through an On-Target, ATF6-Independent Mechanism

Bibiana Rius, Jaleh Mesgarzadeh, Isabelle Romine, Ryan Paxman, Jeffery Kelly, Luke Wiseman,

<h4>SUMMARY</h4> The plasma cell secretion and toxic aggregation of amyloidogenic immunoglobulin light chains (LCs) causes proteotoxicity in Light Chain Amyloidosis (AL). We recently identified endoplasmic reticulum (ER) proteostasis regulators such as compound 147 that reduce secretion and aggregation of LCs implicated in AL (Plate, Cooley et al., 2016). Compound 147 ... Read more >>

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Cited: 0 times

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The unfolded protein response regulator ATF6 promotes mesodermal differentiation.

Heike Kroeger, Neil Grimsey, Ryan Paxman, Wei-Chieh Chiang, Lars Plate, Ying Jones, Peter X Shaw, JoAnn Trejo, Stephen H Tsang, Evan Powers, Jeffery W Kelly, R Luke Wiseman, Jonathan H Lin,

ATF6 encodes a transcription factor that is anchored in the endoplasmic reticulum (ER) and activated during the unfolded protein response (UPR) to protect cells from ER stress. Deletion of the isoform activating transcription factor 6α (ATF6α) and its paralog ATF6β results in embryonic lethality and notochord dysgenesis in nonhuman vertebrates, ... Read more >>

Sci Signal (Science signaling)
[2018, 11(517):]

Cited: 23 times

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Modulating protein quality control.

Lars Plate, Ryan J Paxman, R Luke Wiseman, Jeffery W Kelly,

Small molecules that modulate the unfolded protein response have the potential to treat a variety of human protein misfolding diseases. ... Read more >>

Elife (eLife)
[2016, 5:]

Cited: 4 times

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Criteria for selecting PEGylation sites on proteins for higher thermodynamic and proteolytic stability.

Paul B Lawrence, Yulian Gavrilov, Sam S Matthews, Minnie I Langlois, Dalit Shental-Bechor, Harry M Greenblatt, Brijesh K Pandey, Mason S Smith, Ryan Paxman, Chad D Torgerson, Jacob P Merrell, Cameron C Ritz, Maxim B Prigozhin, Yaakov Levy, Joshua L Price,

PEGylation of protein side chains has been used for more than 30 years to enhance the pharmacokinetic properties of protein drugs. However, there are no structure- or sequence-based guidelines for selecting sites that provide optimal PEG-based pharmacokinetic enhancement with minimal losses to biological activity. We hypothesize that globally optimal PEGylation ... Read more >>

J Am Chem Soc (Journal of the American Chemical Society)
[2014, 136(50):17547-17560]

Cited: 18 times

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Two structural scenarios for protein stabilization by PEG.

Shu-Han Chao, Sam S Matthews, Ryan Paxman, Aleksei Aksimentiev, Martin Gruebele, Joshua L Price,

PEGylation, or addition of poly(ethylene glycol) chains to proteins, is widely used to improve delivery in pharmaceutical applications. Recent studies suggest that stabilization of a protein by PEG, and hence its proteolytic degradability, is sequence-dependent and requires only short PEG chains. Here we connect stabilization by short PEG chains directly ... Read more >>

J Phys Chem B (The journal of physical chemistry. B)
[2014, 118(28):8388-8395]

Cited: 8 times

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